Tuberculosis (TB) is a leading cause of morbidity and mortality among people living with HIV in sub-Saharan Africa. Ethiopia ranks eighth among high-burden TB countries, with an estimated incidence rate of 359 per 100,000, and approximately 1.1 million people are living with HIV. Strong scientific evidence demonstrates that isoniazid preventive therapy (IPT) reduces the risk of TB among HIV-infected individuals. However, implementation of this proven intervention in high-burden settings has been suboptimal. Many barriers to IPT implementation in resource-limited settings have been identified, and impact evaluation of evidence-based interventions to improve IPT initiation, adherence and completion are urgently needed. We propose an innovative cluster randomized trial, the ENhance Initiation and Retention in IPT Care for HIV Study (ENRICH Study), which aims to evaluate the effectiveness of a combination intervention package (CIP) versus standard of care (SOC), to improve IPT initiation, adherence, and completion among HIV-infected individuals enrolled in HIV care at health centers in Ethiopia. The CIP will contain programmatic, structural, and psychosocial components including: 1) use of a clinical algorithm by health care providers; 2) identification of HIV-infected family members eligible for IPT using a family care enrollment form; 3) review of monitoring data on IPT initiation and adherence during monthly multidisciplinary team meetings; 4) reimbursement of transportation costs for monthly clinic visits; and 5) real-time adherence support using interactive voice response via mobile phones and trained peer educators. The specific aims of the study are: 1.Characterize and compare the effectiveness of a combination intervention package with standard of care for IPT provision in Ethiopia. 2. Assess the impact of CIP compared with SOC on HIV-related outcomes. 3. Assess the safety and tolerability of IPT among HIV-infected individuals under routine program conditions in Ethiopia. 4. Identify patient and program characteristics associated with IPT adherence and completion at SOC sites. The team of investigators involved in this proposal includes a diversity of expertise and a wealth of experience in large, collaborative, prospective, multicenter studies in resource-limited countries, particularly in sub- Saharan Africa. The investigators have successfully designed and implemented PEPFAR-supported programs in Ethiopia and elsewhere and have extensive experience in designing and conducting studies on IPT adherence and TB/HIV integration in diverse settings. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is a leading cause of morbidity and mortality among people living with HIV in sub-Saharan Africa. Strong scientific evidence demonstrates that isoniazid preventive therapy (IPT) reduces the risk of TB among HIV-infected individuals; however, implementation of this proven intervention in high-burden, resource-limited settings has been suboptimal. The proposed study will rigorously evaluate the effectiveness of a combination intervention package for IPT provision in HIV programs in Ethiopia; the results will inform programming and policy making across PEPFAR programs.